Background: Cannabis and tobacco use are consistently associated with major depressive disorder (MDD) in conventional observational studies. However, these substances are often co-used, and the independent causal role of cannabis use in risk of MDD remains unclear. Methods: Univariable and multivariable MR (MVMR) were used to explore the total and independent causal effects of genetic liability to tobacco use and cannabis use on MDD. Our primary estimator was the inverse-variance weighted (IVW) method, with other methods as sensitivity analyses. For the exposures, we used genome-wide association study (GWAS) summary statistics among European ancestry individuals for several tobacco use (i.e., smoking initiation, smoking continuation, smoking heaviness) and cannabis use (i.e., cannabis initiation, cannabis use disorder [CUD]) phenotypes. For the outcome, a GWAS of MDD was conducted using individual-level data from UK Biobank. Results: Univariable MR indicated a causal effect of smoking initiation on MDD (odds ratio [OR]IVW = 1.34, 95% confidence interval [CI] = 1.27-1.42), with consistent but weaker evidence for smoking continuation (ORIVW = 1.13, 95% CI = 0.93-1.37) and smoking heaviness (ORIVW = 1.15, 95% CI = 0.99-1.33). There was no clear evidence for a causal effect of cannabis initiation on MDD (ORIVW = 1.00, 95% CI = 0.91-1.11). Univariable MR indicated some evidence for a causal effect of CUD on MDD (ORIVW = 1.14, 95% CI = 1.04-1.25), which attenuated to the null when adjusting for liability to smoking initiation (ORMVMR-IVW = 1.03, 95% CI = 0.97-1.08). Conclusions: This study provides limited evidence for an independent causal effect of cannabis use on MDD, and stronger evidence for an independent causal effect of tobacco use on MDD. Analyses were limited by low power, and future research should triangulate these findings with results from high-quality observational studies.

GT has previously received funding from Grand (Pfizer) for work not related to this project. CB, HS and RW have completed paid consultancy work for Action on Smoking and Health (ASH) for work related to this project. There are no other conflicts of interest to declare.

https://osf.io/bg9vk/

This work is primarily supported by a Society for the Student of Addiction PhD studentship awarded to CB. The funding body had no role the design of the study or collection, analysis, and interpretation of data, or in writing this manuscript. REW is funded by a postdoctoral fellowship from the South-Eastern Norway Regional Health Authority (2020024). GT is funded by a Cancer Research UK Postdoctoral Fellowship (C56067/A21330). This work was supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00032/07).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

UK Biobank received ethics approval from the North West Multi-Centre Research Ethics Committee as a Research Tissue Bank approval (REC; 11/NW/0382). Approval to use these data was sought and approved by UK Biobank (Project ID: 9142). The remaining data draws on publicly available summary statistics from GWAS.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data used in this study comes from several sources. Summary statistics for the tobacco use instruments are available at: https://conservancy.umn.edu/items/ca7ed549-636b-41c0-ae79-97c57e266417. The summary statistics for the cannabis initiation instrument, without 23andMe, are available at: https://www.ru.nl/en/bsi. Access to the summary statistics including 23&Me, requires a separate data transfer agreement from 23andMe. Further information about obtaining access to 23andMe are available from: https://research.23andme.com/dataset-access/. The summary statistics for the CUD instrument, including iPSYCH, are available at: https://medicine.yale.edu/lab/gelernter/stats/. Access to the summary statistics excluding iPSYCH was obtained through request to the authors. Primary data from the UK Biobank resource used to derive the summary statistics for the outcome GWAS of MDD are accessible upon application (https://www.ukbiobank.ac.uk/). The PGC MDD summary statistics are available at: https://pgc.unc.edu/for-researchers/download-results/.

https://github.com/chloeeburke/cantob_mvmr